Search

The article presents a clinical case of a 78-year-old woman who experienced severe oral ulcers and was initially misdiagnosed. She was eventually found to have progressive anemia, thrombocytopenia, and leukocytosis with circulating blasts. Topics discussed include the patient's initial symptoms and examination findings, the progression of her condition, and the diagnostic challenges faced in identifying the underlying cause.

A 42-year-old female with a 15 pack-year history of smoking presented for extraction of root tip #20. A well-defined multilocular radiolucency of the anterior mandible of unknown duration was discovered on a panoramic radiograph (Figure 1). The differential diagnosis of multilocular lesions of the gnathic bones is broad (Table 1). In the present case, lesion borders were considered to be overall well-defined. The unique radiographic presentation which suggested uninvolved alveolar bone between teeth #3.3 and 3.4 (21 and 22) broadened the list of diagnostic possibilities to include multifocal multilocular entities. Despite minimal to no effect of the surrounding dentition, the conspicuous osseous expansion and cortical perforation suggested at least a locally aggressive pathology. Malignant lesions were also considered to a variable extent depending on the type of malignancy. In addition to the radiographic features, the patient's age and the asymptomatic clinical presentation in an otherwise healthy patient were important factors considered in the formulation of the differential diagnosis. Given the close proximity of the epicenter of the lesion to the dentition, odontogenic tumors and cysts with a destructive biologic potential were favored. Ameloblastomas, which frequently harbor BRAF V600E mutations, are the most common odontogenic tumor and typically present as a multilocular radiolucency with variably thick septations imparting a ''honey-comb" appearance.1 They are frequently associated with tooth displacement and resorption, cortical destruction and osseous expansion. While reported synchronously with other odontogenic cysts and tumors, multifocal lesions have not been documented in the literature. The newly described entity, adenoid ameloblastoma (AA) also presents with similar clinical and radiographic features. Unlike conventional ameloblastoma, they are not characterized by BRAF mutations.2 While 2/3 of cases of AA will exhibit dentinoid on histologic examination, approximately 82% of cases will be predominantly radiolucent radiographically. While more commonly a mixed lesion (∼ 75%), calcifying epithelial odontogenic tumors (CEOT) can present as large, expansile multilocular lesions capable of bone erosion, expansion and perforation.3 Rare cases have been reported to involve multiple sites, sometimes synchronously involving the mandible and maxilla.4, 5 Even in cases of multifocal lesions, most patients will not report pain associated with the tumor(s). Osseous expansion can occur, but cortical boundaries are usually respected in cases of CEOT. Other developmental odontogenic entities which can present multifocally include squamous odontogenic tumors, dentigerous cysts, odontogenic keratocysts, orthokeratinized odontogenic cysts, lateral periodontal cysts and their multilocular counterparts, botryoid cysts. With the exception of botryoid cysts, all entities are more frequently unilocular. With expansion of these lesions, cortical thinning may occur, but breaching of the cortices and evident osseous destruction are uncommon. In regard to malignant considerations, odontogenic carcinomas and sarcomas can also present as aggressive multilocular radiolucencies. Lesion borders tend to be ill-defined and infiltrative which contrast with the more demarcated boundaries of this case.6 Given the radiographic findings, the incidental discovery, and completely asymptomatic state of the patient, these entities were considered more unlikely. For similar reasons, solitary plasmacytomas and plasma cell lesions in the setting of multiple myeloma as well as metastatic disease originating from an occult primary were judged less probable, despite their capability of causing expansion and osseous destruction.7, 8 Giant cell lesions including aneurysmal bone cysts (ABC), central giant cell granulomas (CGCG) and brown tumors of hyperparathyroidism (BTH) share similar radiographic findings. In 2017, the World Health Organization recognized ABCs as neoplasms with approximately 70% of cases characterized by the USP6::CDH11 gene fusion. ABCs affect the head and neck region in less than 3% of cases with the mandible representing the most common site (37%), particularly the posterior body and ascending ramus. ABCs can reach a sizable dimension and still remain asymptomatic in some cases. 58-75% are multilocular and up to 15% in some series are multifocal.9, 10 Nonetheless, ABCs remain more common in younger patients with less than 10% of cases occurring over the age of 40.10 CGCG and BTH are histologically identical. A late manifestation of hyperparathyroidism, BTH affects the head and neck region in approximately 4% of cases and both jaws are involved in 23-30% of cases.11 An increase in parathyroid hormone can lead to bone resorption through its effect on the osteoprotegerin–receptor activator of nuclear factor-κB ligand-receptor activator of nuclear factor-κB system. BTH can be multilocular or unilocular with occasionally ill-defined borders. While some cases are asymptomatic, patients may experience signs and symptoms common to locally aggressive lesions such as pain, limited mouth opening, facial swelling and malocclusion. CGCG can present as single or multiple unilocular to multilocular generally well-defined radiolucencies. They are components of many syndromes including cherubism, Noonan syndrome, Jaffe-Campanacci syndrome and neurofibromatosis type I. KRAS, TRPV4 , or FGFR1 mutations are identified in 70% of sporadic CGCG.12 CGCG have a variable symptomatology profile depending on size and location of the lesion. However, they do remain overwhelmingly more common in younger patients with more than 75% of cases diagnosed in individuals younger than 30 years of age. Cemento-ossifying fibromas (OF), now characterized as cemento-ossifying dysplasia in the 2022 WHO classification, are radiolucent to mixed lesions that can reach a sizable dimension causing bucco-lingual expansion as well as downward bowing and thinning of the inferior mandibular cortex.2 They frequently affect the premolar to molar region; however, they are usually unilocular and rarely multifocal (5% of sporadic cases). Pain is uncommon (10% of cases), but swelling is frequent (90% of cases).13 5% of sporadic cases harbor mutations of the tumor suppressor gene CDC73 associated with hyperparathyroidism-jaw tumor syndrome. Cone beam CT was performed. A lesion measuring approximately 7.1 cm x 3.4 cm x 1.7 cm (Figure 2A, B) demonstrating severe bone resorption and cortical perforation (Figure 2C) was removed and submitted to pathology. Microscopic examination revealed a mass of fibrovascular connective tissue containing vital bone, a robust lymphocytic infiltrate, and numerous cells with large oval nuclei, indistinct cell borders and a pale "foamy" cytoplasm (Figure 3A). Upon examination at higher power, foci of eosinophils were noted, and the pale cells exhibited folded or "kidney bean" shaped nuclei (Figure 3B). CD1a (Figure 4A) and S-100 staining (Figure 4B) confirmed that these were Langerhans cells. Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, characterized by aberrant function and differentiation or proliferation of cells of the mononuclear phagocyte system. The disease is more common in children and adolescents, with an annual incidence of 4.6 cases per 1 million children under 15 years of age and a male-to-female ratio of 1.2:1. A higher incidence has been reported for Hispanics, and a lower incidence in African Americans. It can also be seen in adults, with an incidence of 1-2 cases per million, usually presenting in the 4th decade.14 There is currently a debate regarding the nature of LCH. The benign histologic appearance of the Langerhans cells, the associated inflammatory infiltrate, and a characteristic cytokine storm support a lesion of inflammatory origin, while the clonality, somatic activating gene mutations in the mitogen-activated protein kinase (MAPK) pathway (the BRAF V600E mutation), and shared mutations with hematopoietic precursor cells favor its classification as a myeloid neoplastic disorder.14 Indeed, the extent and severity of the different forms of LCH depend on the state of differentiation of the precursor cell in which the somatic MAPK activating mutations arise.14 Monostotic or polyostotic eosinophilic granuloma of bone (the chronic focal form) has an excellent prognosis and arises from mutations late in dendritic cell differentiation, whereas chronic disseminated histiocytosis (chronic multifocal, also known as Hand-Schüller-Christian Disease) involves bone, skin and viscera and acute disseminated histiocytosis (Letterer-Siwe Disease) shows prominent visceral, cutaneous and bone marrow involvement and a poor prognosis as a result of mutations arising earlier in blood dendritic cell precursors or hematopoietic stem cells, respectively.15 Also favoring a neoplastic process is the association of LCH with other malignancies, with frequencies varying from 2.6% in children to 32% in adults. The most common hematologic malignancy reported is acute myeloid leukemia (AML), often occurring years after LCH, but others include lung and thyroid carcinomas and acute lymphoblastic leukemia (ALL). Coincident LCH and ALL share the same oncogenic mutations or have identical T-cell receptor or immunoglobulin rearrangements, suggesting a clonal relationship between the two.16 Pulmonary LCH (PLCH), which is the most common manifestation in adults, is considered a specific type of LCH. Although PLCH cells have similar histopathologic characteristics as LCH, most proliferations are polyclonal. Pulmonary LCH is also strongly related to smoking as more than 90% of patients are smokers and cessation has led to remission without treatment in some cases.17 [ABSTRACT FROM AUTHOR]

Objective: To establish and test a clinician‐reported outcome measure of oral lichen planus (OLP): OLP Investigator global assessment (IGA). Methods: OLP IGA scale was tested with retrospective data from clinical practice and a phase II clinical trial. A comparison of the OLP IGA score with patient‐reported outcomes was completed. Results: Clinical Practice: The mean (SD) OLP IGA score (0–4) in 107 OLP patients was 1.8 (1.0) with correlation of 0.25–0.48 (p value 0.01 – <0.0001) with symptom scores. There was a significant increase in OLP symptoms based on OLP IGA score. Clinical Trial: The mean (SD) OLP IGA score in 137 research participants was 2.5 (1.2) with correlation of 0.43–0.52 (all p values <0.0001) with symptoms scores. There was a significant increase in OLP symptoms based on OLP IGA score. Forty‐seven (35%) participants in the phase 2 study had an improvement in the OLP IGA score of ≥2. There were significant improvements in all symptoms scores in relation to the change in IGA score. Conclusions: The OLP IGA is designed to assess changes in symptomatic OLP lesions and is appropriate for use across the full range of symptomatic OLP severity and represents a scale with utility in clinical practice and clinical trials. [ABSTRACT FROM AUTHOR]

A core outcome set (COS) is the minimum agreed-on data set required to be measured in interventional trials. To date, there is no COS for oral lichen planus (OLP). This study describes the final consensus project that brought together the results of the previous stages of the project to develop the COS for OLP. The consensus process followed the Core Outcome Measures in Effectiveness Trials guidelines and involved the agreement of relevant stakeholders, including patients with OLP. Delphi-style clicker sessions were conducted at the World Workshop on Oral Medicine VIII and the 2022 American Academy of Oral Medicine Annual Conference. Attendees were asked to rate the importance of 15 outcome domains previously identified from a systematic review of interventional studies of OLP and a qualitative study of OLP patients. In a subsequent step, a group of OLP patients rated the domains. A further round of interactive consensus led to the final COS. The consensus processes led to a COS of 11 outcome domains to be measured in future trials on OLP. The COS developed by consensus will help reduce the heterogeneity of outcomes measured in interventional trials. This will allow future pooling of outcomes and data for meta-analyses. This project showed the effectiveness of a methodology that could be used for future COS development. [ABSTRACT FROM AUTHOR]

There is a lack of consensus regarding clinician- and patient-reported oral lichen planus (OLP) outcomes. The World Workshop on Oral Medicine Outcomes Initiative for the Direction of Research (WONDER) Project aims to develop a core outcome set (COS) for OLP, which would inform the design of clinical trials and, importantly, facilitate meta-analysis, leading to the establishment of more robust evidence for the management of this condition and hence improved patient care. Ovid MEDLINE, Embase, CINAHL, CENTRAL, and Clinicaltrials.gov were searched for interventional studies (randomized controlled trials, controlled clinical trials, and case series including ≥5 participants) on OLP and oral lichenoid reactions published between January 2001 and March 2022 without language restriction. All reported primary and secondary outcomes were extracted. The searches yielded 9,135 records, and 291 studies were included after applying the inclusion criteria. A total of 422 outcomes were identified. These were then grouped based on semantic similarity, condensing the list to 69 outcomes. The most frequently measured outcomes were pain (51.9%), clinical grading of the lesions (29.6%), lesion size/extension/area (27.5%), and adverse events (17.5%). As a first step in developing a COS for OLP, we summarized the outcomes that have been used in interventional studies over the past 2 decades, which are numerous and heterogeneous. [ABSTRACT FROM AUTHOR]

This study aimed to explore the lived experience of patients with oral lichen planus (OLP) and investigate what treatment-related outcomes are the most important to them and should be included in a core outcome set (COS) for OLP. A qualitative study involving focus group work with 10 participants was conducted. Interviews with each focus group were held twice: session 1 explored the lived experience of patients with OLP, and session 2 allowed patients to review a summary of the outcome domains used in the OLP literature to date. The discussions were recorded, transcribed verbatim, and analyzed using framework analysis. In session 1, 4 themes and 8 sub-themes emerged from the data analysis. An additional outcome, 'knowledge of family and friends,' was suggested in session 2. We have gained valuable insight into the lived experience of patients with OLP via this qualitative study. To our knowledge, this study is the first to explore the patient perspective on what should be measured in clinical trials on OLP, highlighting an important additional suggested outcome. This additional outcome will be voted upon in a consensus process to determine a minimum COS for OLP. [ABSTRACT FROM AUTHOR]

Basement membrane invasion defines malignant transformation of surface premalignancy. Treatment of oral squamous cell carcinoma (OSCC) cells with the synthetic vitamin A derivative, fenretinide (4HPR), induces numerous cancer-preventive effects including suppression of basement membrane invasion, elimination of anchorage-independent growth, disruption of actin cytoskeletal components and inhibition of the invasion-enabling focal adhesive kinase. The purpose of this study was to elucidate 4HPR's effects on additional invasion-relevant mechanisms including matrix metalloproteinase (MMP) activation and function, cell–extracellular matrix (ECM) attachments and interaction with a kinase that is essential for the epithelial–myoepithelial transformation i.e. c-Jun NH2-terminal kinase (JNK). Our data revealed that 4HPR binds with high affinity to the ATP-binding site of all three JNK isoforms with concurrent suppression of kinase function. Additional studies showed 4HPR treatment inhibited both OSCC cell–ECM adhesion and MMP activation and function. JNK downregulation and induced expression studies confirmed that the JNK3 isoform conveyed that largest impact on OSCC migration and invasion. Biodegradable polymeric implants formulated to preserve 4HPR's function and bioavailability were employed to assess 4HPR's chemopreventive impact on an OSCC tumor induction model. These studies revealed 4HPR local delivery significantly inhibited OSCC tumor size, mitotic indices and expression of the endothelial marker, erythroblast transformation-specific-related gene with concurrent increases in tumor apoptosis (cleaved caspase-3). Collectively, these data show that 4HPR suppresses invasion at multiple sites including 'outside-in' signaling, cell–ECM interactions and suppression of MMPs. These functions are also essential for physiologic function. Regulation is therefore essential and reinforces the pharmacologic advantage of local delivery chemopreventive formulations.. [ABSTRACT FROM AUTHOR]

Introduction: The subepithelial connective tissue graft (SCTG) and flap combination is a highly predictable root coverage procedure, with low complication rates. To our knowledge, this article reports the first case of two late SCTG complications, epithelial cell discharge, and subsequent epidermal inclusion cyst (EIC) formation. Case Presentation: A 35‐year‐old male presented with a 3‐mm deep Miller Class II recession defect on the mandibular right canine and mesial root of mandibular right first molar. A mild discomfort was reported at 8 weeks after envelope flap+SCTG in #27. At 4 months after the procedure, the patient presented with persistent discomfort and minimally compressible recipient site diffuse swelling with discharge, which was cytologically diagnosed as normal epithelial cells. One year postoperatively, enlargement of the lesion was seen, and excisional biopsy was performed simultaneously with SCTG in #30. The lesion was diagnosed as EIC. At 8 months follow‐up, the site healed uneventfully, the patient remained asymptomatic, and the site exhibited scar formation and no recurrence of the lesion. Conclusion: This report highlights epithelial cell discharge and EIC formation as a rare yet possible SCTG complication and emphasizes the importance of an excisional biopsy as the means to obtain a definitive diagnosis and manage this complication. [ABSTRACT FROM AUTHOR]

The molecular findings in Ewing sarcoma have greatly expanded in recent years. Furthermore, this is particularly true for the subset termed "Ewing-like" undifferentiated round cell sarcomas in which new translocations have been reported since the fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone. Amid this expanding genetic landscape, we report a case of extraskeletal undifferentiated round cell "Ewing-like" sarcoma in a 27-year-old female. The patient presented with a large lung mass accompanied on staging imaging by deposits suspicious for metastatic disease in the humerus, calvarium, and lymph nodes of the neck and chest. Biopsy of the lung mass revealed a densely packed monotonous proliferation of round, uniform neoplastic cells with scant cytoplasm. By immunohistochemistry, the tumor cells were diffusely positive for CD99, synaptophysin, TLE1, EMA, and MUC4 and negative for FLI1, PAX7, AE1/3, S100, SOX10, WT1, p63, desmin, and HMB45. Fluorescence in situ hybridization demonstrated rearrangement of the EWSR1 gene. Next-generation sequencing based assay revealed an EWSR1-CREB3L1 fusion. Taken together, the histomorphologic and molecular findings were considered consistent with an undifferentiated round cell sarcoma with an EWSR1-CREB3L1 fusion. Although described in entities such as sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and small cell osteosarcoma, this has not been previously described in undifferentiated round cell ("Ewing-like") sarcoma. This finding adds to the growing list of undifferentiated round cell sarcomas with Ewing-like morphologic phenotype–associated fusion genes and may contribute to further defining and characterizing the different subset of tumors in the Ewing family of tumors. [ABSTRACT FROM AUTHOR]

Objectives: The Oral Lichen Planus Investigator Global Assessment (OLP IGA) outcome is a new disease specific measure assessing the severity of OLP. Based on literature review on existing OLP measures, results from a recent Phase II OLP study and expert discussions, a hypothesized conceptual framework for a new 5-point IGA specific to erosive OLP has been developed, built on the general principles of IGAs used in dermatology. Based on OLP expert reviews and recommendations, the current OLP IGA considers the heterogeneity of the clinical characteristics of symptomatic OLP lesions to accurately document their clinical severity assessing 2 characteristics of OLP representing: ulceration and erosions/erythema (redness). To determine the symptom association with the OLP IGA score in Oral Medicine practices in Charlotte, NC and Cork, Ireland from October 2020 to October, 2021. Methods: Successive OLP patients seen for a standard of care visit in Charlotte (n=44) or Cork (n=50) were enrolled. Each patient completed the symptom assessment with the OLPSSM questionnaire and OLP NRS scores of pain and symptoms. The IGA score (0-4) was completed by a calibrated examiner. IGA scores of 3 and 4 represent ulcerative forms of OLP. Results: The mean (SD) age of OLP patients was 64.4 (11.2) years. The mean OLP IGA score was 1.7 (1.0) with frequency (%) for each score: 0=3 (3.2%); 1=45 (47.9%), 2=28 (29.8%), 3=12 (12.8) and 4=6 (6.4%). The correlation of the IGA score with symptoms scores ranged from 0.43-0.59 (p values=<0.0001). The mean (SD) score for OLP symptoms included: current level of soreness (0-10) was 2.5 (2.7); worst pain from OLP from the last 24 hours (0-10) was 2.7 (2.7); and current level of pain (0-4) was 1.4 (1.2). There was an incremental increase with an increase of IGA score for all symptom scores (p values all <0.0006). Conclusions: There was a strong association of the IGA OLP score with patient symptom scores. This new clinician reported outcome measures is key to establish a primary outcome measure in interventional clinical trial and to be used in clinical practice assessing reliable meaningful changes in OLP. [ABSTRACT FROM AUTHOR]

Objectives: Oral lichen planus (OLP) is a common immune-mediated condition affecting the mucous membranes and skin with a prevalence of approximately 0.5% in the general population. In numerous clinical trials for OLP management, pain as measured by a visual analogue scale (VAS) remains one of the most common tools to assess symptomatology. However, it is often used alone with no emphasis placed on non-pain related symptoms. The Oral Lichen Planus Symptom Severity Measure (OLPSSM) is a well-defined assessment tool to characterize symptom severity when performing activities of daily living. The goal of this study was to determine which descriptor most accurately described OLP symptom experience. More specifically, the objectives were to evaluate the frequency of pain and non-pain related symptoms in patients. The trends regarding descriptors used and their association with different patient-reported severity measures assessed by the OLPSSM were also explored. Methods: Following IRB approval, successive patients diagnosed with OLP, who met inclusion criteria, and who attended the oral medicine clinics in Charlotte (n=44) or Cork (n=50) were prospectively enrolled into the study. Each patient who participated answered the OLPSSM questionnaire previously developed at the time of their visit. Patients were also asked to choose a one word descriptor which best described their symptoms. These were limited to the previous descriptors reported by patient interviews in the development of OLPSSM: soreness, pain, sensitivity, burning, irritation, and tenderness. The OLPSSM questionnaire has been implemented as standard of care for patients with OLP followed at the Charlotte oral medicine clinic since July 2020. Thus, retrospective data from 49 patients followed at the Charlotte clinic who had previously answered the questionnaire and chosen the most relevant word descriptor was also included (total n=143). Qualitative and quantitative statistics were obtained using the SAS Analytics Software. Results: The majority (77%) of patients were female. The mean age was 65.2 years (range: 35-83 years). Most patients (77%) presented with a non-ulcerative form of OLP, but only 2% of patients had white lesions only without any erythema or erosion. The frequency of most common descriptors used consisted of soreness (35%), burning (18%), irritation (18%), tenderness (12%), sensitivity (11%) and pain (6%), and two patients declined to answer this question as they reported they had always been asymptomatic. There was a statistically significant difference (Mantel-Haenszel Chi-Square test, p=0.01) in the frequency of use of descriptive terminology between the Cork and the Charlotte cohorts. Patients in Charlotte more frequently used burning or pain (24% and 8% respectively) than in Cork (6% and 4% respectively). 48% of Irish patients chose soreness as the best descriptor for their symptoms. The tabulated scores of symptoms when performing different activities in the past 24 hours (OLPSSM total score for questions 1-7) ranged between 0 and 18 with a mean of 4.2, representing relatively mild symptoms. Non parametric analysis via Kruskal-Wallis tests revealed statistically significant differences based on the most common descriptor chosen with the total tabulated scores of symptoms when performing different activities in the past 24 hours (OLPSSM1-7, p=0.016), overall severity of symptoms in the past 24 hours (OLPSSM10, p=0.028), and severity of symptoms over the past week (OLPSSM11, p=0.036). There was an overall tendency observed amongst patients reporting burning or pain as their most common symptom to also report higher scores in the OLPSSM1-7, OLPSSM10, and OLPSSM11. In contrast, patients using sensitivity or irritation as the best descriptor showed a tendency towards lower scores on the OLPSSM questionnaire. Additionally, the prospective group (n=94) was questioned on their current level of soreness (anchored scale of 0-10), current level of pain (Likert 5-point scale from none to worse pain imaginable), and the worse pain from OLP in the past 24h (0-10). Statistically significant differences were noted between groups (common descriptors used) when evaluating these patient responses (p=0.014, p=0.05, p=0.036, respectively). Patients choosing pain as the best descriptor showed a tendency to report higher scores for these questions. Conclusions: This study is the first to assess the symptom descriptor which is most reflective of overall OLP symptoms. Only 6% of patients in this multicenter cohort study chose pain to best describe their symptoms, with soreness (35%) being the most common symptom descriptor chosen. This is an important observation since many studies base their symptom assessment on pain using a VAS. Additionally, patients who reported burning or pain as the most accurate OLP symptom descriptor had higher symptoms scores. Future goals consist of contextualizing these subjective measures with objective assessments of clinical disease severity and to evaluate the overall effect on quality of life. [ABSTRACT FROM AUTHOR]

Locoregional recurrence of oral squamous cell carcinoma (OSCC) dramatically reduces patient survival. Further, as many OSCC recurrences are inoperable, radiotherapy and chemotherapy with or without biological adjuncts are the remaining treatment options. Although the tumors may initially respond, radiotherapy- and chemotherapy-resistant cancer stem cells (CSC) can readily repopulate OSCC tumors. Currently, following the initial OSCC treatment, patients are closely monitored until a recurrence or a second primary is detected. Identification of agents with complementary mechanisms to suppress CSC tumorigenic functions could change this passive approach. The goals of this study were twofold: (1) develop and validate CSC-enriched (CSCE) OSCC cell lines and (2) identify chemopreventive agents that obstruct multiple CSCE protumorigenic pathways. CSCE cultures, which were created by paclitaxel treatment followed by three tumorsphere passes, demonstrated CSC characteristics, including increased expression of stem cell and inflammatory genes, increased aldehyde dehydrogenase (ALDH) activity, and enhanced in vitro / in vivo proliferation and invasion. Three chemopreventives, fenretinide, tocilizumab, and reparixin, were selected due to their distinct and complementary CSC-disruptive mechanisms. The CSCE selection process modulated the cells' intermediate filaments resulting in an epithelial-predominant (enhanced cytokeratin, proliferation, IL6 release) line and a mesenchymal-predominant (upregulated vimentin, invasive, IL8 release) line. Our results confirm that 4HPR binds with appreciably higher affinity than Wnt at the Frizzled binding site and significantly inhibits CSC-enabling Wnt-β-catenin downstream signaling. Notably, combination fenretinide-tocilizumab-reparixin treatment significantly suppressed IL6 and IL8 release, stem cell gene expression, and invasion in these diverse CSCE populations. These promising multiagent in vitro data provide the basis for our upcoming in vivo CSCE tertiary chemoprevention studies., (©2019 American Association for Cancer Research.)